Patent GB-802901-A (GB)
Title: New basically substituted heterocyclic compounds and process for their manufacture
Filed: 1955-03-03
Abstract: The invention comprises compounds of the general formula <FORM:0802901/IV (b)/1> and acid addition and quaternary salts thereof, wherein R is an amino group disubstituted by alkyl and/or cycloalkyl groups or by an alkylene group or an alkylene residue interrupted by a hetero atom, each of these substituents not containing more than 6 carbon atoms, and A represents an alkylene residue containing not more than 6 carbon atoms.  The compounds may optionally be substituted in the benzene rings by halogen atoms, or amino groups, or alkyl or alkoxy groups of 1-6 carbon atoms.  The compounds are prepared by treating an 11 - keto - dibenzo - [b : f] - thia - [1] - aza - [4] - cycloheptadiene - [2 : 6] compound, in which the benzene rings may be substituted or unsubstituted as indicated above, with a reactive ester of an alcohol of the formula R-A-OH or a quaternary compound thereof.  The reaction is suitably carried out by reacting the dibenzocycloheptadiene compound in the form of a metal salt or in the presence of a condensing agent capable of forming a metal salt therewith with an ester of the alcohol R-A-OH derived from a strong acid such as an hydrohalic acid or a sulphonic acid such as p-toluene sulphonic acid.  The products may be quaternated with an alkyl halide, dialkyl sulphate or sulphonic acid alkyl ester.  The products, which are therapeutically active are suitably used in the form of salts such as a hydrohalide, sulphate, nitrate, phosphate, thiocyanate, acetate, propionate, oxalate, malonate, succinate, malate, methane sulphonate, ethane sulphonate, hydroxyethane sulphonate or benzene or toluene sulphonate, or as a salt with a therapeutically active acid.  Examples describe the preparation of 10-substituted 11-keto - dibenzo - [b : f] - thia - [1] - aza - [4] - cycloheptadienes - 2 : 6], wherein the 10 - substituent group is (1) diethylaminoethyl; (2) dimethylaminoethyl; (3) diethylaminopropyl; (4) a -pyrrolidinopropyl; and (5) a - and b -methyl-b -dimethylaminoethyl; also the 2-chloro-, 6-chloro-, 7-chloro-, 8-chloro- and 8-amino-derivatives of (2); the 6-chloro-, 7-chloro-, 8-chloro and 7 : 8-dichloro-derivatives of 10 - (a  - dimethylamino - propyl) - 11 - keto-dibenzo - [b : f] - thia - [1] - aza - [4] - cycloheptadiene - [2 : 6]; the 8 - chloro - derivative of (3) and the corresponding quaternary ethiodide and the 7-chloro-derivative of (1).  Starting materials.  11-Keto-dibenzo-[b : f]-thia - [1] - aza - [4] - cycloheptadiene - [2 : 6] and derivatives thereof used as starting materials such as the 2-, 6-, 7- and 8-chloro and 7 : 8-dichloro derivatives are made by intramolecular condensation of the appropriate 2-amino - diphenylsulphide - 21 - carboxylic acid or a functional derivative thereof.  2-Amino-4-chloro - diphenylsulphide - 21 - carboxylic acid methyl ester and the corresponding 5-chloro- and 4 : 5-dichloro compounds are made by treating 2 : 5 - dichloro - nitrobenzene 2 : 4 - dichloronitrobenzene and 2 : 4 : 5 - trichloro - nitrobenzene respectively with the sodium salt of methyl thiosalicylate in methanol and reducing the resulting nitro compound. 2-Aminodiphenyl - sulphide - 4 - chloro - 21 - carboxylic acid methyl ester is prepared by heating o-chloro-nitrobenzene with 5-chloro-thiosalicyclic acid methyl ester and reducing the resulting nitro compound.ALSO:Anti-histaminic preparations comprise compounds of the general formula <FORM:0802901/VI/1> or acid addition or quaternary salts thereof, wherein R is an amino group, disubstituted by alkyl or cycloalkyl groups or by an alkylene group or by an alkylene group interrupted by a hetero atom, each of these substituents not containing more than 6 carbon atoms, A is an alkylene residue of 1 to 6 carbon atoms and the benzene rings may optionally bear halogen, amino or alkyl or alkoxy substituents of 1 to 6 carbon atoms, admixed with a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, parenteral or topical administration.  The preparations may be in the form of tablets, dragees, salves, creams, solutions, suspensions or emulsions. Suitable diluents include water, gelatine, lactose, starches, magnesium stearate, vegetable oils, talc, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly and cholesterol.  Preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers may also be added.  Specified active compounds are the 10-substituted 11 - keto - dibenzo - [b : f] - thia - [1] - aza - [4] - cycloheptadienes - [2 : 6] wherein the 10-substituents are (1) diethylaminoethyl; (2) dimethylaminoethyl; (3) diethylaminopropyl; (4) g -pyrrolidinopropyl; and (5) a - and b - methyl - b  - dimethylaminoethyl groups; also the 2-chloro-, 6-chloro-, 7-chloro-, 8-chloro and 8-amino-derivatives of (2); the 6-chloro-, 7-chloro-, 8-chloro and 7 : 8-dichloro-derivatives of 10 - (g  - dimethylaminopropyl) - 11 - keto - dibenzo - [b : f] - thia - [1] - aza - [4] - cycloheptadiene-[2 : 6]; the 8-chloro-derivative of (3) and the corresponding quaternary ethiodide, and the 7-chloro-derivative of (1).